The purpose of this project is to analyze physiological and pathological aspects of the renin-angiotensin system, including the effects of AII in circulatory homeostasis, fetal development pituitary and gonadal function. AII mediates the increase in aldosterone secretion during sodium restriction, but the adrenal effects of the peptide are dependent on the sensitivity of the glomerulosa zone to AII. Previous studies in the rat have demonstrated that the adrenal responsiveness to AII depends on trophic effects of the peptide and the modulatory effect of other regulators such as dopamine, atrial natriuretic factor (ANF) and somatostatin (SRIF). Elucidation of the mechanisms by which these factors modulate the effects of AII required a precise knowledge of the mechanism of action of AII. The cellular effects of AII include calcium mobilization and phospholipid turnover. In isolated rat adrenal glomerulosa cells, AII was shown to cause translocation and presumably activation of protein kinase C (PKC). Studies directed to determine the role of PKC in the steroidogenic action of AII provided two lines of evidence indicating that PKC does not mediate the stimulation of aldosterone secretion by AII. First, depletion of endogenous PKC by prolonged incubation with phorbol esters had no effect on AII-stimulated aldosterone responses. Second, the aldosterone response to AII is potentiated when PKC is maximally translocated to the membrane by a phorbol ester. These data suggest that PKC activation by AII is involved in such functions as cell growth rather that the direct stimulation of aldosterone secretion. Further studies have been performed to characterize the novel AII binding sites found in the rat and mouse fetus. These receptors are widely distributed throughout skeletal muscle and connective tissue during the last third of fetal life and are reduced by 80% one day after birth. The role of AII in fetal development is under study in secondary cultures of cells prepared from fetal skin. These cells have fibroblast-like characteristics and contain abundant AII receptors. Incubation of the cultures with AII resulted in rapid increase in cytosolic calcium and inositol phosphate formation. The prominent and transient expression of functional AII receptors in the fetus suggest a role of AII during intrauterine development.
